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Objectives To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. Study design This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. Results WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. Conclusions Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. Trial registration ClinicalTrials.gov: NCT00063063.

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Objective: The study goal was to evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among extremely low birth weight (ELBW) infants. Study design: This is a retrospective analysis of ELBW (<1000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network sites between January 2000 and June 2007. Infants were tracked until death or 18 to 22 months' corrected age. Infants who died between NICU discharge and the 18- to 22-month follow-up visit were classified as post-NICU discharge mortality (P-NDM). Association of maternal and infant risk factors with P-NDM was determined using logistic regression analysis. A prediction model with 6 significant predictors was developed and validated. Results: There were 5364 infants who survived to NICU discharge; 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. P-NDM rate was 22.3 per 1000 ELBW infants. In the prediction model, African American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intrapartum antibiotics was associated with decreased risk of P-NDM. Conclusion: We identified African American race, unknown medical insurance, and prolonged NICU stay as risk factors associated with P-NDM among ELBW infants.

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BackgroundExtremely preterm infants (EPT, < 29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-33 6/7 weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.

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Background: We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants.
Objective: This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death.
Study Design: The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed.
Results: All the four definitions were associated with greater number of days on MV and days on O<inf>2</inf>. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death.
Conclusions: The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

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BACKGROUND: Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families. METHODS: We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences. RESULTS: The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days. CONCLUSIONS: We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

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Background: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization.
Methods: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored.
Results: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so.
Conclusion: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

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OBJECTIVE:
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
METHODS:
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
RESULTS:
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
CONCLUSIONS:
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

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IMPORTANCE Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS Randomized 2 × 2 factorial clinical trial in neonates (-36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES The primary outcomewas death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42%female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95%CI, 0.68-1.25] ; adjusted absolute risk difference, -1.0% [95%CI, -10.2%to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95%CI, 0.68-1.26] ; adjusted absolute risk difference, -3.1% [95% CI, -12.3%to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3%at 33.5°C for 72 hours, 34.5%at 32.0°C for 72 hours, 34.4%at 33.5°C for 120 hours, and 28.2%at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C.